Although marine ladder polyethers are extremely toxic compounds, they are also known to have antifungal and anticancer properties. The biosynthesis of these compounds is proposed to occur via an epoxide-opening cascade reaction, and several biomimetic reactions have been developed to synthesize portions of these molecules. In general, a cascade reaction is a consecutive series of chemical reactions that proceed via reactive intermediates and create multiple new bonds in one sequential process. These reactions allow for the rapid creation of molecular complexity and provide a more efficient synthetic route than building a molecule in an iterative fashion. In particular, the cascade reaction described in this proposal will enable the synthesis of fused polyether ring systems with 1,3-diaxial methyl groups, a motif that is present in many ladder polyethers. Despite the prevalence of this motif in these compounds, no cascade reactions have been reported that create rings containing this substitution pattern. This proposal also describes the application of this cascade reaction to the synthesis of a portion of brevisulcenal F and several other marine ladder polyethers. Brevisulcenal F is a marine ladder polyether natural product that was identified as a component of a harmful algal bloom (HAB) off the coast of New Zealand in 1998. It is one of the largest and most toxic marine polyethers that has been isolated. Therefore, its synthesis would provide material to study its unique bioactivity and determine possible applications for treating disease. Importantly, gambierol, a related ladder polyether, has been used as a chemical probe to study receptors implicated in the molecular basis of Alzheimer's disease. In this proposal, a strategy for the synthesis of the B-D and F-I rings of brevisulcenal F is outlined in which several rings are created iteratively, and the cascade process is then applied to the synthesis of the remaining rings. A similar strategy is presented for portions of maitotoxin, gambierol, gambieric acid A, and brevetoxin B. It is expected that the success of this proposal will set the stage for the total synthesis of these molecules and provide material to study their mechanisms of action.